scholarly journals Temporal and Quantitative Analysis of Atherosclerotic Lesions in Diet-Induced Hypercholesterolemic Rabbits

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Qi Yu ◽  
Yafeng Li ◽  
Ahmed Bilal Waqar ◽  
Yanli Wang ◽  
Bingqiao Huang ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Rabbit Model ◽  
Cellular Component ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
High Cholesterol ◽  
Ideal Model ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Transmission Electron

The diet-induced atherosclerotic rabbit is an ideal model for atherosclerosis study, but temporal changes in atherosclerotic development in hypercholesterolemic rabbits are poorly understood. Japanese white rabbits were fed a high-cholesterol diet to induce sustained hypercholesterolemia, and each group of 10–12 animals was then sacrificed at 6, 12, 16, or 28 weeks. The rabbit aortas were harvested, and the sizes of the gross and intima atherosclerotic lesions were quantified. The cellular component of macrophages (Mφs) and smooth muscle cells (SMCs) in aortic intimal lesions was also quantified by immunohistochemical staining, and the correlation between plasma cholesterol levels and the progress of atherosclerotic lesions was studied. The ultrastructure of the atherosclerotic lesions was observed by transmission electron microscopy (TEM). Widely variable atherosclerotic plaques were found from 6 weeks to 28 weeks, and the lesional progress was closely correlated with cholesterol exposure. Interestingly, a relatively reduced accumulation of Mφ, an increased numbers of SMCs, and a damaged endothelial layer were presented in advanced lesions. Moreover, SMCs were closely correlated with cholesterol exposure and lesional progress for the whole period. Cholesterol exposure directly determines atherosclerotic progress in a rabbit model, and the changes in the cellular component of advanced lesions may affect plaque stability in an atherosclerotic rabbit model.

scholarly journals Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Li Zhang ◽  
Prashant Rajbhandari ◽  
Christina Priest ◽  
Jaspreet Sandhu ◽  
Xiaohui Wu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
High Cholesterol ◽  
Cholesterol Levels ◽  
Expression Of Genes ◽  
Lysine Residues ◽  
Genetic Deletion

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.

Effects of dietary flaxseed on vascular contractile function and atherosclerosis during prolonged hypercholesterolemia in rabbits

2006 ◽  
Vol 291 (6) ◽  
pp. H2987-H2996 ◽  
Author(s):  
C. M. C. Dupasquier ◽  
A.-M. Weber ◽  
B. P. Ander ◽  
P. P. Rampersad ◽  
S. Steigerwald ◽  
...  
Keyword(s):  
Vascular Function ◽  
Contractile Function ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Relaxation Response ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Beneficial Effects ◽  
Atherosclerotic Lesions

Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol- and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the anti-atherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary cholesterol until 16 wk. This functional impairment was not prevented by including flaxseed in the high-cholesterol diet. Aortic rings from the cholesterol-fed rabbits exhibited an impaired relaxation response to acetylcholine at all time points examined. Including flaxseed in the high-cholesterol diet completely normalized the relaxation response at 6 and 8 wk and partially restored it at 16 wk. No significant changes in the relaxation response induced by sodium nitroprusside were observed in any of the groups. In summary, dietary flaxseed is a valuable strategy to limit cholesterol-induced atherogenesis as well as abnormalities in endothelial-dependent vasorelaxation. However, these beneficial effects were attenuated during prolonged hypercholesterolemic conditions.

scholarly journals High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr–/– Mice: Impact on Cognitive Function

2020 ◽  
Vol 78 (1) ◽  
pp. 97-115
Author(s):  
Jade de Oliveira ◽  
Daiane F. Engel ◽  
Gabriela C. de Paula ◽  
Danúbia B. dos Santos ◽  
Jadna B. Lopes ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Familial Hypercholesterolemia ◽  
Blood Brain Barrier ◽  
Plasma Cholesterol ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
Wild Type ◽  
High Cholesterol ◽  
Cholesterol Levels ◽  
Hypercholesterolemic Diet

Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. Results: A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

The synthesis of soluble and Insoluble elastin in chicken aorta as a function of development and age. Effect of a high cholesterol diet

1979 ◽  
Vol 57 (11) ◽  
pp. 1273-1280 ◽  
Author(s):  
F. W. Keeley
Keyword(s):  
High Cholesterol Diet ◽  
Aortic Tissue ◽  
Cholesterol Feeding ◽  
High Cholesterol ◽  
Transient Effect ◽  
Adult Chicken ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Old Adult ◽  
Tissue Cholesterol

The synthesis of soluble elastin, newly synthesized insoluble elastin and total accumulated insoluble elastin was measured in aortic tissue of chickens ranging in age from the 11-day embryo to the adult chicken. Synthesis of soluble elastin reached a maximum in the 1st week after hatching, then decreased rapidly with a second transient increase between 4 and 6 weeks and thereafter decreased continuously until synthesis could no longer be detected in the 35-week-old adult. A portion of this newly synthesized soluble elastin was insolubilized even during 1 h of incubation by a β-aminopropionitrile-inhibited mechanism. Total insoluble elastin accumulated rapidly in aortic tissue in the late embryonic stages and reached a plateau about 1 week after hatching, after which time the proportion of the protein in the tissue remained constant. Synthesis of soluble elastin and total insoluble elastin was also determined in aortic tissue of chickens raised on a diet containing 2% cholesterol for 14 weeks after hatching. This cholesterol-rich diet had an early, but transient effect on the synthesis of soluble elastin, shifting the age of maximal synthesis to 1 to 2 weeks after hatching. However, by 6 to 8 weeks on the diet there was no difference in soluble elastin synthesis between normal and cholesterol-fed groups. Although prolonged cholesterol feeding resulted in serum cholesterol levels 10 times normal, aortic tissue cholesterol levels 3 times normal and grossly visible atherosclerotic lesions, no reinitiation of soluble elastin synthesis or alteration in the quantity and character of insoluble aortic elastin could be detected.

Simvastatin Reduces Expression and Activity of Lipoprotein-Associated Phospholipase A2 in the Aorta of Hypercholesterolaemic Atherosclerotic Rabbits

2009 ◽  
Vol 37 (4) ◽  
pp. 1029-1037 ◽  
Author(s):  
Z Qiao ◽  
J Ren ◽  
H Chen
Keyword(s):  
Atherosclerotic Lesion ◽  
Statin Treatment ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Local Inflammatory Response ◽  
Plaque Instability ◽  
Significant Difference

Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to atherosclerotic plaque instability and subsequent sudden coronary death. Statins are associated with decreased stroke risk and may improve stability of atherosclerotic plaques. The present study investigated the effect of simvastatin on expression of Lp-PLA2 levels in atherosclerotic plaques and on Lp-PLA2 activity in atherosclerotic aortas. Rabbits were a fed chow (control group) or a high-cholesterol diet (atherosclerosis group) for 12 weeks. An additional group on the high-cholesterol diet received simvastatin (5 mg/kg per day) for the last 4 weeks (simvastatin group). Lp-PLA2 activity in plasma and atherosclerotic aortas was significantly higher in the atherosclerosis group than in the control group and, consistent with this, abundant Lp-PLA2 protein was detected in plaques in the atherosclerosis group. Simvastatin significantly reduced Lp-PLA2 activity in plasma and aorta tissue, and reduced Lp-PLA2 protein level in atherosclerotic plaques. Whereas there was no significant difference in total atherosclerotic lesion area between simvastatin and atherosclerosis groups, simvastatin significantly reduced macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Thus, statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques. This was associated with attenuation of the local inflammatory response and improved plaque stability.

Cholesterol-induced Thrombogenicity of the Vessel Wall: Inhibitory Effect of Fluvastatin

2002 ◽  
Vol 87 (04) ◽  
pp. 748-755 ◽  
Author(s):  
Marina Camera ◽  
Vincenzo Toschi ◽  
Carmen Comparato ◽  
Roberta Baetta ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Serum Cholesterol ◽  
Transcriptional Activation ◽  
Vessel Wall ◽  
Arterial Wall ◽  
Thrombus Formation ◽  
Plasma Cholesterol ◽  
Elevated Serum ◽  
Rabbit Model ◽  
Cholesterol Levels ◽  
Platelet Deposition

SummaryHigh cholesterol levels are a known risk factor for coronary events. The molecular links between high serum cholesterol and the increased thrombogenicity of the arterial wall are still matter of investigation. In the present study we investigate the relationship between plasma cholesterol, thrombus formation and TF expression in a atherosclerotic rabbit model.Hypercholesterolemic rabbits showed a pronounced TF staining as well as NF-κB activation in the aortic arch. A consistent vessel wall platelet deposition was also observed. Treatment with fluvastatin reduced lipid accumulation, TF overexpression (-60%), NF-κB activation, and platelet deposition (-56%). In vitro studies showed that the drug upregulated IκBa in unstimulated as well as in TNFa-stimulated cells and also impaired the TNF-α-induced Cdc42 prenylation, indicating that fluvastatin interferes with the transcriptional activation of TF gene.These results indicate that the prothrombotic phenotype of arterial wall, associated with elevated serum cholesterol levels, is mediated by TF overexpression. Fluvastatin treatment reduces the prothrombotic tendency by inhibiting TF synthesis.

scholarly journals Phosphatidylcholine transfer protein regulates size and hepatic uptake of high-density lipoproteins

2005 ◽  
Vol 289 (6) ◽  
pp. G1067-G1074 ◽  
Author(s):  
Michele K. Wu ◽  
David E. Cohen
Keyword(s):  
Plasma Cholesterol ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Cholesterol Diet ◽  
Wild Type ◽  
High Cholesterol ◽  
High Fat ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein ◽  
Atp Binding Cassette

Phosphatidylcholine transfer protein (PC-TP) is a steroidogenic acute regulatory-related transfer domain protein that is enriched in liver cytosol and binds phosphatidylcholines with high specificity. In tissue culture systems, PC-TP promotes ATP-binding cassette protein A1-mediated efflux of cholesterol and phosphatidylcholine molecules as nascent pre-β-high-density lipoprotein (HDL) particles. Here, we explored a role for PC-TP in HDL metabolism in vivo utilizing 8-wk-old male Pctp−/− and wild-type littermate C57BL/6J mice that were fed for 7 days with either chow or a high-fat/high-cholesterol diet. In chow-fed mice, neither plasma cholesterol concentrations nor the concentrations and compositions of plasma phospholipids were influenced by PC-TP expression. However, in Pctp−/− mice, there was an accumulation of small α-migrating HDL particles. This occurred without changes in hepatic expression of ATP-binding cassette protein A1 or in proteins that regulate the intravascular metabolism and clearance of HDL particles. In Pctp−/− mice fed the high-fat/high-cholesterol diet, HDL particle sizes were normalized, whereas plasma cholesterol and phospholipid concentrations were increased compared with wild-type mice. In the absence of upregulation of hepatic ATP-binding cassette protein A1, reduced HDL uptake from plasma into livers of Pctp−/− mice contributed to higher plasma lipid concentrations. These data indicate that PC-TP is not essential for the enrichment of HDL with phosphatidylcholines but that it does modulate particle size and rates of hepatic clearance.

scholarly journals Cholesterol in pregnancy: a review of knowns and unknowns

2011 ◽  
Vol 4 (4) ◽  
pp. 147-151 ◽  
Author(s):  
Änne Bartels ◽  
Keelin O'Donoghue
Keyword(s):  
Cardiovascular Disease ◽  
Vitamin D ◽  
Fetal Development ◽  
Plasma Cholesterol ◽  
Adult Population ◽  
The Body ◽  
High Cholesterol ◽  
Cholesterol Levels ◽  
Growing Body ◽  
In Pregnancy

Cholesterol forms part of every cell in the human body, and also helps make and metabolize hormones, bile acids and vitamin D. Human plasma cholesterol levels are determined by production in the liver and by dietary intake. Lipoproteins carry cholesterol around the body, and facilitate it crossing the placenta. Cholesterol is carefully monitored in the non-pregnant adult population, where its association with atherosclerosis and cardiovascular disease is well understood. Although it is known that cholesterol rises in pregnancy, at present it is not routinely measured or treated. The effects of maternal high cholesterol on pregnancy and on fetal development are not yet fully understood. However, a growing body of evidence from animal and human studies suggests adverse consequences of high cholesterol levels in pregnancy.

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